Salvianolic Acid A Protects the Kidney against Oxidative Stress by Activating the Akt/GSK-3β/Nrf2 Signaling Pathway and Inhibiting the NF-κB Signaling Pathway in 5/6 Nephrectomized Rats

Abstract

Salvianolic acid A (SAA) is a bioactive polyphenol extracted from Salviae miltiorrhizae Bunge, which possesses a variety of pharmacological activities. In our previous study, we have demonstrated that SAA effectively attenuates kidney injury and inflammation in an established animal model of 5/6 nephrectomized (5/6Nx) rats. However, there has been limited research regarding the antioxidative effects of SAA on chronic kidney disease (CKD). Here, we examined the antioxidative effects and underlying mechanisms of SAA in 5/6Nx rats. The rats were injected with SAA (2.5, 5, and 10 mg·kg-1·d-1, ip) for 28 days. Biochemical, flow cytometry, and Western blot analyses showed that SAA significantly increased the activities of total superoxide dismutase (T-SOD), glutathione peroxidase (GPx), and catalase (CAT) and lowered the levels of malondialdehyde (MDA), reactive oxygen species (ROS), and NADPH oxidase 4 (NOX-4) in a dose-dependent manner in 5/6Nx rats and in H2O2-induced HK-2 cells in vitro. Moreover, SAA enhanced the activation of the protein kinase B/glycogen synthase kinase-3β/nuclear factor-erythroid-2-related factor 2 (Akt/GSK-3β/Nrf2) signaling pathway in a dose-dependent manner and subsequently increased the expression of heme oxygenase-1 (HO-1) in the kidney of 5/6Nx rats, which were consistent with those obtained in H2O2-induced HK-2 cells in vitro shown by Western blot analysis. Furthermore, SAA significantly increased the expression of intranuclear Nrf2 and HO-1 proteins compared to HK-2 cells stimulated by LPS on the one hand, which can be enhanced by QNZ to some extent; on the other hand, SAA significantly lowered the expression of p-NF-κB p65 and ICAM-1 proteins compared to HK-2 cells stimulated by H2O2, which can be abrogated by ML385 to some extent. In conclusion, our results demonstrated that SAA effectively protects the kidney against oxidative stress in 5/6Nx rats. One of the pivotal mechanisms for the protective effects of SAA on kidney injury was mainly related with its antioxidative roles by activating the Akt/GSK-3β/Nrf2 signaling pathway and inhibiting the NF-κB signaling pathway.

Activation of the AMPK-SIRT1 pathway contributes to protective effects of Salvianolic acid A against lipotoxicity in hepatocytes and NAFLD in mice

“…Therefore, Sal A-stimulated Nrf2 activation might be involved in the protection against NAFLD via antioxidative stress. Additionally, the anti-inflammatory role of Sal A has been reported in renal, brain, and cardiac tissues (Yuan et al, 2017;Zhang et al, 2018;Zhang et al, 2019). A recent study revealed that Sal A supplementation alleviated HFD-induced hepatic inflammation (Ding et al, 2016).…”

Inflammation and Premature Ageing in Chronic Kidney Disease

“…Furthermore, uremic toxins correlate positively with NF-κB expression and negatively with NRF2 expression in peripheral blood mononuclear cells [123]. Accordingly, rats undergoing 5/6 nephrectomy also show an impaired activation of NRF2 in the kidneys [124]. Conversely, the NRF2 agonist bardoxolone reduces tubular cell mitochondrial damage and improves redox balance and mitochondrial function in a CKD mouse model [125].…”

Role of the KEAP1-NRF2 Axis in Renal Cell Carcinoma

“…In this context, a transitory activation of the NRF2 axis in response to stress is beneficial for the normal tissue, again supporting the idea that the NRF2 role in promoting a malignant phenotype depends on its chronic hyperactivation. In fact, treatment with salvianolic acid, through AKT activation and consequent GSK-3β inhibition, induces NRF2 nuclear accumulation and transcription of target genes that protect the kidney epithelium from the oxidative stress produced during chronic kidney disease (CKD) [134]. Curiously, GSK-3β is generally overexpressed in RCC, where it supports tumor cells proliferation and it has been pointed out as a promising target for RCC treatment, with 9-ING-41 inhibitor in clinical trial [135], partially contrasting with the NRF2 accumulation and contribution to RCC progression.…”